Obesity and diabetes have reached epidemic proportions in our society. Brown adipose tissue (BAT), which burns fat to produce heat, represents a promising target to combat these diseases. We have recently discovered that his tone deacetylase 3 (HDAC3), an enzymatic modulator of the epigenome, regulates critical lipid metabolism genes in BAT. I hypothesize that manipulation of HDAC3 in brown adipose will improve metabolic function. My first specific aim is to characterize HDAC3-dependent transcriptional regulation in BAT to determine which gene networks are controlled by HDAC3 under basal conditions and following cold exposure. Factors mediating HDAC3 recruitment to these genes will be identified in genome-wide analyses, and validated by gain and loss-of-function studies. My second specific aim is to investigate the physiological role of HDAC3 in BAT bioenergetics processes. I will examine the impact of HDAC3 on lipid metabolism, mitochondrial uncoupling capacity, and cold tolerance in cells and live animals. The proposed experiments will address the epigenetic and transcriptional mechanisms by which HDAC3 regulates organism energy expenditure. The results of this study will advance the basic understanding of how mammals cope with environmental stresses through coordinated changes in bioenergetics networks. Furthermore, this work has the potential to translate into novel therapies targeting conserved, fat-burning pathways for the prevention and treatment of metabolic disorders. PUBLIC HEALTH RELEVANCE: Obesity and diabetes have reached epidemic proportions in our society. The goal of the proposed research is to more completely understand the regulation of fundamental, fat-burning processes in an effort to develop novel therapies with which to combat these metabolic diseases.